1. Field of the Invention
The present invention relates to a method for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid by resolving racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an optically active amine compound, novel optically active amine compound therefor and its production process.
2. Description of Related Art
Optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is a useful intermediate compound of pharmaceuticals for urinary incontinence as described in WO97/14672 and also of agrochemicals.
There have been reported a method in which racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is resolved with optically active xcex1-methylbenzylamine (J. Med. Chem., 1996, 39, 4592-4601) and a method in which racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is optically resolved with brucine and followed by repeated recrystallizations (J. Chem. Soc., 1951, 2329-2332).
An object of the present invention is to provide a diastereomer salt comprising a specific optically active amine and optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which is suitable for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid having good optical purity,
another object of the invention is to provide a process for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in industrially advantageous manner,
further objects of the invention are to provide
novel optically active amine compounds suitable for optical resolution,
intermediate compounds for producing the optically active amines, and
processes for producing the intermediate compounds.
The present invention provides:
1. A diastereomer salt of formula (1): 
xe2x80x83wherein each asymmetric carbon atom denoted by the symbol * is independently in S configuration or R configuration,
R1 represents a lower alkyl group which may be substituted with a hydroxy group, or an optionally substituted aryl group,
R2 represents a lower alkyl group which may be substituted with a hydroxy group, or an optionally substituted aralkyl group, and
R3 represents a lower alkyl group which may be substituted with a hydroxy group, a hydrogen atom, a cyclohexyl group, or an optionally substituted aralkyl group,
provided that R1 and R2 are not the same, and when R1 is a phenyl group and R2 is a methyl group, R3 is not a hydrogen atom;
2. A method for producing a diastereomer salt of formula (1) as defined above, which comprises contacting racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2): 
xe2x80x83with an optically active amine of formula (3): 
wherein the symbol *, R1, R2, and R3 respectively represent the same as defined above to form diastereomer salt(s), and separating said diastereomer salt of formula (1);
3. A method for producing an optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2xe2x80x2): 
xe2x80x83wherein an asymmetric carbon atom denoted by the symbol * is in S configuration or R configuration,
which comprises treating the salt of formula (1) as defined above, with an acid, or a base and an acid;
4. An optically active amine compound of formula (4): 
xe2x80x83wherein an asymmetric carbon atom denoted by the symbol * is in S configuration or R configuration,
R11 represents an aryl group which may be substituted with at least one group selected from a, C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogen atom,
R21 represents a C1-C4 alkyl group, or an aralkyl group which may be substituted, and
R31 is a 3-benzyloxyphenyl group or a 4-benzyloxyphenyl group, or a salt thereof;
5. A method for producing an optically active amine compound of formula (4) as defined above, or a salt thereof, which comprises:
reducing an imine compound of formula (7); 
xe2x80x83wherein the symbol *, R11, R21 and R31 respectively have the same meaning as defined above, to a reduction reaction;
6. An imine compound of formula (7) as defined above,
7. A method for producing an imine compound of formula (7) as defined above, which comprises:
reacting an optically active amine of formula (5): 
xe2x80x83wherein the symbol * denotes an asymmetric carbon atom,
R11 and R21 respectively represent the same as defined above, with a benzyloxybenzaldehyde of formula (6):
R31xe2x80x94CHOxe2x80x83xe2x80x83(6)
wherein R31 represents a 3-benzyloxyphenyl group or a 4-benzyloxyphenyl group;
8. An optically active amine compound of formula (8): 
xe2x80x83wherein X1 represents a halogen atom, or a lower alkyl group,
X2 to X5 are the same or different and independently represent a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group,
R22 represents a lower alkyl group, and
R32 represents an aryl group substituted with at least one group selected from a lower alkyl group, a lower alkoxy group, an aryl group, and an aryloxy group;
9. A method for producing an optically active amine compound of formula (8) as defined above, which comprises:
subjecting an imine compound of formula (11): 
xe2x80x83wherein X1 to X5, R22 and R32 are the same as defined above, to a reduction reaction.
10. An imine compound of formula (11) as defined above; and
11. A method for producing an imine compound of formula (11) as defined above, which comprises:
reacting an optically active amine compound of formula (9): 
xe2x80x83wherein X1 to X5 and R22 are the same as defined above, with an aldehyde of formula (10):
R32xe2x80x94CHOxe2x80x83xe2x80x83(10)
wherein R32 represents the same as defined above.
First a descritpion will be made to the diastereomer salt of formula (1).
Racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2) can be prepared by a known method as disclosed in J. Chem. Soc., 1951, 2329-2332 or the like.
The substituent groups R1, R2, and R3 of the optically active amine compound of formula (3) will be explained below.
Examples of the lower alkyl group which may be substituted with a hydroxy group, in R1, R2, and R3 include a C1-C4 alkyl group which may be substituted with a hydroxy group.
Specific examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a t-butyl group, a sec-butyl group, an i-butyl group, a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 2-hydroxy-2-methylpropyl group and the like.
In R3, the hydroxy group which may be present on the alkyl moiety of the alkyl group which may be substituted with a hydroxy group is not on a carbon atom which is bound with the nitrogen atom.
Examples of the optionally substituted aryl group, in R1 include a phenyl group, a naphthyl group and the like, all of which may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogen atom.
The C1-C4 alkyl group on the aromatic ring of the aryl groups includes a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a t-butyl group, a sec-butyl group and an i-butyl group.
The C1-C4 alkoxy group on the aromatic ring of the aryl groups includes a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a t-butoxy group and the like.
Examples of the halogen atom on the aromatic ring include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Specific examples of the optionally substituted aryl group include a phenyl group, a naphthyl group, a 4-methylphenyl group,
a 4-ethylphenyl group, a 4-propylphenyl group, a 4-isopropylphenyl group,
a 4-t-butylphenyl group, a 2,5-dimethylphenyl group,
a 2,4,6-trimethylphenyl group, a 2-fluorophenyl group,
a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group,
a 3-chlorophenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenyl group,
a 2,3-dichlorophenyl group, a 4-bromophenyl group,
a 2-methoxyphenyl group, a 4-methoxyphenyl group,
a 2-ethoxyphenyl group, a 2-propoxyphenyl group,
a 3,4-dimethoxyphenyl group, a 2-methoxy-5-fluorophenyl group and the like.
The optionally substituted aralkyl group, in R2 and R3 include a C7-C12 aralkyl group
of which aryl group may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group, a halogen atom, a C6-C10 aryl group, a C6-C10 aryloxy group, a C7-C12 aralkyl group and a C7-C12 aralkyloxy group, the last four of which may be substituted on each aromatic ring with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group and a halogen atom, and
of which alkyl group (e.g., a methyl or ethyl group) may be substituted with a hydroxy group.
The aryl groups in the above-described aryl, aryloxy, aralkyl and aralkyloxy groups include a C6-C10 aryl group such as a phenyl or naphthyl group.
The alkyl moiety, in the aralkyl group, which may be substituted with a hydroxyl group include a methyl group or ethyl group, a hydroxymethyl group or hydroxyethyl group.
The C1-C4 alkyl group, the C1-C4 alkoxy group and the halogen atom, all of which may be present on the aryl group include the same groups as specified above.
Specific examples of the aryloxy group include a phenoxy, 1-naphthoxy and 2-naphthoxy group and the like.
Specific examples of the aralkyl groups include a benzyl group, a phenylethyl group, 1-naphtylmethyl group, 2-naphtylmethyl group and the like.
Specific examples of the aralkyloxy group include a benzyloxy group, 1-naphtylmethoxy group, 2-naphtylmethoxy group and the like.
Specific examples of the optionally substituted aralkyl group, in R2 and R3 include a benzyl group, a naphthylmethyl group,
a 3-methylbenzyl group, a 4-methylbenzyl group, a 4-ethylbenzyl group,
a 4-propylbenzyl group, a 4-isopropylbenzyl group, a 4-t-butylbenzyl group,
a 2,5-dimethylbenzyl group, a 2,4,6-trimethylbenzyl group,
a 2-fluorobenzyl group, a 3-fluorobenzyl group, a 4-fluorobenzyl group,
a 2-chlorobenzyl group, a 3-chlorobenzyl group, a 4-chlorobenzyl group,
a 2,4-dichlorobenzyl group, a 2,3-dichlorobenzyl group,
a 4-bromobenzyl group, a 2-methoxybenzyl group, a 3-methoxybenzyl group,
a 4-methoxybenzyl group, a 2-ethoxybenzyl group, a 2-propoxybenzyl group,
a 3,4-dimethoxybenzyl group, a 2-methoxy-5-fluorobenzyl group,
a 2-phenylethyl group, an xcex1-hydroxybenzyl group,
an xcex1-hydroxy-4-methylbenzyl group, an xcex1-hydroxy-4-methoxybenzyl group,
an xcex1-hydroxy-4-nitrobenzyl group, an xcex1-hydroxy-4-chlorobenzyl group,
a 3-phenoxybenzyl group, a 4-phenoxybenzyl group, a 3-phenylbenzyl group,
a 4-phenylbenzyl group, a 3-benzyloxybenzyl group, a 4-benzyloxybenzyl group and the like.
Specific examples. of the optically active amine (3) include optically active isomers of xcex1-ethylbenzylamine, xcex1-propylbenzylamine,
xcex1-isopropybenzylamine, xcex1,4-dimethylbenzylamine,
xcex1,2,5-trimethylbenzylamine, xcex1,2,4,6-tetramethylbenzylamine,
xcex1-methyl-4-isopropylbenzylamine, 2-fluoro-xcex1-methylbenzylamine,
3-fluoro-xcex1-methylbenzylamine, 4-fluoro-xcex1-methylbenzylamine,
4-bromo-xcex1-methylbenzylamine, 2-chloro-xcex1-methylbenzylamine,
3-chloro-xcex1-methylbenzylamine, 4-chloro-xcex1-methylbenzylamine,
2,3-dichloro-xcex1-methylbenzylamine, 2,4-dichloro-xcex1-methylbenzylamine,
2-methoxy-xcex1-methylbenzylamine, 4-methoxy-xcex1-methylbenzylamine,
2-ethoxy-xcex1-methylbenzylamine, 3,4-dimethoxy-xcex1-methylbenzylamine,
5-fluoro-2-methoxy-xcex1-methylbenzylamine, xcex1,xcex2-diphenylethylamine,
1-phenyl-2-(p-tolyl)ethylamine, xcex1-phenyl-xcex2-(3-methoxyphenyl)ethylamine,
xcex1-phenyl-xcex2-(4-chlorophenyl)ethylamine, xcex1,xcex3-diphenylpropylamine,
xcex1-methyl-1-naphthylamine, xcex1-methyl-2-naphthylmethylamine,
N-benzyl-xcex1-methylbenzylamine,
N-(2-naphthylmethyl)-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1-methylbenzylamine,
N-(4phenylbenzyl)-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-1-phenyl-2-(p-tolyl)ethylamine,
N-(4-phenylbenzyl)-1-phenyl-2-(p-tolyl)ethylamine,
N-benzyl-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-chlorobenzyl)-xcex1-methylbenzylamine,
N-(4-chlorobenzyl)-xcex1-methylbenzylamine,
N-(3-nitrobenzyl)-xcex1-methylbenzylamine,
N-(4nitrobenzyl)-xcex1-methylbenzylamine,
norephedrine,
2-amino-1-phenyl-1-butanol,
2-amino-3-methyl-1-phenyl-1-butanol,
2-amino-1-(4-methylphenyl)-1-propanol,
2-amino-1-(4-nitrophenyl)-1-propanol,
2-amino-1-(4-chlorophenyl)-1-propanol,
2-amino-1,2-diphenylethanol,
2-amino-1-phenyl-2-(p-tolyl)ethanol,
2-amino-1-phenyl-2-(4-chlorophenyl)ethanol,
2-amino-1-phenyl-2-(4-methoxyphenyl)ethanol,
N-benzyl-2-amino-1-phenyl-1-propanol,
N-benzyl-2-amino-1-phenyl-1-butanol,
N-benzyl-2-amino-3-methyl-1-phenyl-1-butanol,
N-benzyl-2-amino-1-(4-methylphenyl)-1-propanol,
N-benzyl-2-amino-1-(4-nitrophenyl)-1-propanol,
N-benzyl-2-amino-1-(4-chlorophenyl)-1-propanol,
N-benzyl-2-amino-1,2-diphenylethanol,
N-benzyl-2-amino-1-phenyl-2-(p-tolyl)ethanol,
N-benzyl-2-amino-1-phenyl-2-(4-chlorophenyl)ethanol,
N-benzyl-2-amino-1-phenyl-2-(4-methoxyphenyl)ethanol,
N-(3-benzyloxybenzyl)-2-amino-1-phenyl-1-propanol,
N-(4-phenylbenzyl)-2-amino-1-phenyl-1-propanol,
N-(2-naphthylmethyl)-2-amino-1-phenyl-1-propanol,
N-(4-methylbenzyl)-2-amino-1-phenyl-1-propanol,
N-(3-chlorobenzyl)-2-amino-1-phenyl-1-propanol,
N-(4-nitrobenzyl)-2-amino-1-phenyl-1-propanol,
N-(4-methoxybenzyl)-2-amino-1-phenyl-1-propanol,
N-(2,5-dimethoxybenzyl)-2-amino-1-phenyl-1-propanol,
N-(3-methoxybenzyl)-2-amino-1-phenyl-1-propanol, and the like.
Among these optically active amines (3), preferred are optical isomers of xcex1-4-dimethylbenzylamine,
N-benzyl-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-xcex1-methylbenzylamine,
N-(2-naphthylmethyl)-xcex1-methylbenzylamine,
N-(3-chlorobenzyl)-xcex1-methylbenzylamine, 1-phenyl-2-(p-tolyl)ethylamine,
N-benzyl-1-phenyl-2-(p-tolyl)ethylamine,
N-benzyl-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine, norephedrine and the like.
More preferred are
an optically active amine compound of formula (3), wherein R1 is a phenyl group, R2 is a 4-methylbenzyl group and R3 is a benzyl group,
an optically active amine compound of formula (3), wherein R1 is a methyl group, R2 is an xcex1-hydroxybenzyl group and R3 is a hydrogen atom,
an optically active amine compound of formula (3), wherein R1 is a 2,4-dichlorophenyl group, R2 is a methyl group and R3 is a 3-benzyloxybenzyl group,
an optically active amine compound of formula (3), wherein R1 is a 2,4-dichlorophenyl group, R2 is a methyl group and R3 is a 4-phenylbenzyl group, which are N-benzyl-1-phenyl-2-(p-tolyl)ethylamine,
N-(3-benzyloxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine, and norephedrine.
The diastereomer salt of formula (1) as defined above can be produced by a process which comprises contacting racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2) with an optically active amine of formula (3), typically in a solvent, to obtain diastereomer salt(s), and isolating the desired diastereomer salt of formula (1).
The amount of the optically active amine (3) to be used is usually approximately from 0.2 to 3 moles, preferably approximately from 0.4 to 1.5 moles per mol of racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2).
The diastereomer salt of formula (1) formed in the resulting reaction mixture is usually precipitated, wherein the reaction mixture is usually in solution form and optionally a solvent may be used for dissolving said reaction mixture.
Precipitation of the desired salt may be accomplished on standing, stirring, inoculating of seed crystals, cooling and/or concentrating said solution, and precipitated salts are usually isolated, for example, by filtration or the like, and optionally followed by washing and/or drying.
Contacting the 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2) with the optically active amine (3), standing, stirring, cooling, and/or concentrating of the solution of the diastereomer salts are usually conducted within a temperature range of from a melting point of the solution to the boiling point of the solvent, if employed, or typically between from xe2x88x9220 to 60xc2x0 C.
Examples of the solvent to be used include alcohols such as methanol, ethanol, isopropyl alcohol or the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or the like, ethers such as diethyl ether, t-butyl methyl ether, n-butyl ether, tetrahydrofuran or the like, esters such as ethyl acetate, aliphatic hydrocarbons such as n-hexane, n-heptane, cyclohexane or the like, aromatic hydrocarbons such as benzene, toluene, xylene or the like, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, chlorobenzene or the like, aprotic polar solvents such as dimethylformamide, acetonitrile or the like, and water, etc. The solvent may be used alone or as a mixture thereof.
The amount of the solvent to be used may be optionally set depending on the kind of the optically active amine (3), the kind of the solvent and the like, but is usually within the range of from 1 to 50 parts by weight per 1 part by weight of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2).
Examples of the diastereomer salt of formula (1) include salts comprising optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2xe2x80x2) having either S or R configuration with respect to the asymmetric carbon atom designated by *, and optically active amine of formula (3) as specified above having either S or R configuration with respect to the asymmetric carbon atom designated by *.
The optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2xe2x80x2) can be obtained by a method, which comprises treating the salt of formula (1) as defined above, with an acid, or a base and an acid.
Optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2xe2x80x2) can be obtained, for example, by contacting the diastereomer salt (1) with an aqueous acid solution, or an acid and water, extracting the resulting aqueous acid layer with, a hydrophobic solvent, and then concentrating the extract.
Alternatively, the diastereomer salt (1) may be contacted with an aqueous basic solution. After extracting the resulting aqueous basic layer with a hydrophobic solvent, the separated aqueous layer is acidified with an acid, extracting the aqueous acid layer with a hydrophobic solvent and then concentrating the extract to yield the optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2xe2x80x2).
Specific examples of the acid to be used include an inorganic acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid or the like. Among these acids, hydrochloric acid and sulfuric acid are particularly preferred.
The amount of the acid to be used is usually approximately from 1 to 200 moles, preferably approximately from 2 to 20 moles per mol of the diastereomer salt (1).
Specific examples of the base to be used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or the like, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide or the like, alkali carbonates such as sodium carbonate, potassium carbonate or the like, alkali hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate or the like, etc.
The amount of the: base to be used is usually approximately from 1 to 200 moles, preferably approximately from 2 to 20 moles per mol of the diastereomer salt (1).
Specific examples of the hydrophobic solvent to be used for extraction in the present invention include ethers such as diethyl ether, t-butyl methyl ether, n-butyl ether, tetrahydrofuran or the like, esters such as ethyl acetate or the like, aliphatic hydrocarbons such as n-hexane, n-heptane, cyclohexane or the like, aromatic hydrocarbons such as benzene, toluene, xylene or the like, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, chlorobenzene or the like. The hydrophobic solvent may be used alone or as a mixture thereof.
The amount of the hydrophobic solvent to be used for extraction varies depending on the kind of the optically active amine (3) of the diastereomer salt, the kind of the solvent and the like, but it is usually within the range of from 1 to 200 parts by weight per 1 part by weight of the diastereomer salt (1).
The amount of water, or aqueous acidic solution to be used for the dissolution of the diastereomeric salt (1) varies depending on the kind of the optically active amine (3) of the diastereomer salt and the like, but it is usually within the range of from 1 to 200 parts by weight per 1 part by weight of the diastereomer salt (1).
The extraction is usually conducted at a temperature range of from the melting point to the boiling point of water and the solvent to be used, preferably approximately from 0 to 60xc2x0 C.
According to the present invention, the optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which is useful as an intermediate for producing pharmaceuticals or agrochemicals, can be obtained in good optical purity in an industrial scale.
The optically active amine compound of formula (3) include novel optically active amine compounds of formulae (4) and (8).
In the novel optically active compound of formula (4), the aryl group which may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogen atom, in R11 include the same group as defined for R1 above.
The optionally substituted aralkyl group and the C1-C4 alkyl group, in R21 respectively represent the same groups as defined for R2 above.
R31 represents a 3-benzyloxyphenyl group or a 4-benzyloxyphenyl group.
Specific examples of the optically active amine compound (4) or a salt thereof include optically active isomers of
N-(3-benzyloxybenzyl)-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1-ethylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1-propylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1-isopropylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1,4-dimethylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1,2,5-trimethylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1,2,4,6-tetramethylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1-methyl-4-isopropylbenzylamine,
N-(3-benzyloxybenzyl)-2-4-fluoro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-3-fluoro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-4-fluoro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-4-bromo-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-3-chloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-4-chloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-2-methoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-4-methoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-2-ethoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-3,4 dimethoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-5-fluoro-2-methoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzyl)-xcex1,xcex2-diphenylethylamine,
N-(3-benzyloxybenzyl)-1-phenyl-2-(p-tolyl)ethylamine,
N-(3-benzyloxybenzyl)-xcex1-phenyl-xcex2-(3-methoxyphenyl)ethylamine,
N-(3-benzyloxybenzyl)-xcex1-phenyl-xcex2-(4-chlorophenyl)ethylamine,
N-(3-benzyloxybenzyl)-xcex1,xcex3-diphenylpropylamine,
N-(3-benzyloxybenzyl)-xcex1-methyl-1-naphthylamine,
N-(3-benzyloxybenzyl)-xcex1-methyl-2-naphthylmethylamine,
N-(4-benzyloxybenzyl)-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1-ethylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1-propylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1-isopropylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1,4-dimethylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1,2,5-trimethylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1,2,4,6-tetramethylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1-methyl-4-isopropylbenzylamine,
N-(4-benzyloxybenzyl)-2-fluoro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-3-fluoro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-4-fluoro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-4-bromo-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-3-chloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-4-chloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-2-methoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-4-methoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-2-ethoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-3,4-dimethoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-5-fluoro-2-methoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzyl)-xcex1,xcex2-diphenylethylamine,
N-(4-benzyloxybenzyl)-1-phenyl-2-p-tolyl)ethylamine,
N-(4-benzyloxybenzyl)-xcex1-phenyl-xcex2-(3-methoxyphenyl)ethylamine,
N-(4-benzyloxybenzyl)-xcex1-phenyl-xcex2-(4-chlorophenyl)ethylamine,
N-(4-benzyloxybenzyl)-xcex1,xcex3-diphenylpropylamine,
N-(4-benzyloxybenzyl)-xcex1-methyl-1-naphthylamine,
N-(4-benzyloxybenzyl)-xcex1-methyl-2-naphthylmethylamine, and salts thereof with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or the like.
Preferred are
optically active amine compounds of formula (4), wherein R11 is a phenyl group and R21 is a methyl group, and
optically active amine compounds of formula (4), wherein R11 is a 2,4-dichlorophenyl group and R21 is a methyl group.
The optically active amine compound (4) can be obtained, for example, by a process, which comprises subjecting the imine compound of formula (7) to a reduction reaction.
In the imine compound of formula (7), R11, R21 and R31 are as defined above for the optically active amine compound of formula (4).
Specific examples of the imine compound (7) include:
N-(3-benzyloxybenzylidene)xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1-ethylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1-propylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1-isopropylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1,4-dimethylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1,2,5-trimethylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1,2,4,6-tetramethylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1-methyl-4-isopropylbenzylamine,
N-(3-benzyloxybenzylidene)-2-fluoro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-3-fluoro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-4-fluoro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-4-bromo-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-3-chloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-4-chloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-2-methoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-4-methoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-2-ethoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-3,4-dimethoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-5-fluoro-2-methoxy-xcex1-methylbenzylamine,
N-(3-benzyloxybenzylidene)-xcex1,xcex2-diphenylethylamine,
N-(3-benzyloxybenzylidene)-1-phenyl-2-(p-tolyl)ethylamine,
N-(3-benzyloxybenzylidene)-xcex1-phenyl-xcex2-(3-methoxyphenyl)ethylamine,
N-(3-benzyloxybenzylidene)-xcex1-phenyl-xcex2-(4-chlorophenyl)ethylamine,
N-(3-benzyloxybenzylidene)-xcex1,xcex3-diphenylpropylamine,
N-(3-benzyloxybenzylidene)-xcex1-methyl-1-naphthylamine,
N-(3-benzyloxybenzylidene)-xcex1-methyl-2-naphthylmethylamine,
N-(4-benzyloxybenzylidene)-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-xcex1-ethylbenzylamine,
N-(4-benzyloxybenzylidene)-xcex1-propylbenzylamine,
N-(4-benzyloxybenzylidene)-xcex1-isopropylbenzylamine,
N-(4-benzyloxybenzylidene)-xcex1,4-dimethylbenzylamine,
N-(4-benzyloxybenzylidene)-xcex1,2,5-trimethylbenzylamine,
N-(4-benzyloxybenzylidene)-xcex1,2,4,6-tetramethylbenzylamine,
N-(4-benzyloxybenzylidene)xcex1-methyl-4-isopropylbenzylamine,
N-(4-benzyloxybenzylidene)-2-fluoro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-3-fluoro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-4-fluoro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-4-bromo-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-3-chloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-4-chloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-2-methoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-4-methoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-2-ethoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-3,4-dimethoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-5-fluoro-2-methoxy-xcex1-methylbenzylamine,
N-(4-benzyloxybenzylidene)-xcex1,xcex2-diphenylethylamine,
N-(4-benzyloxybenzylidene)-1-phenyl-2-(p-tolyl)ethylamine,
N-(4-benzyloxybenzylidene)-xcex1-phenyl-xcex2-(3-methoxyphenyl)ethylamine,
N-(4-benzyloxybenzylidene)-xcex1-phenyl-xcex2-(4-chlorophenyl)ethylamine,
N-(4-benzyloxybenzylidene)-xcex1,xcex3-diphenylpropylamine,
N-(4-benzyloxybenzylidene)-xcex1-methyl-1-naphthylamine,
N-(4-benzyloxybenzylidene)-xcex1-methyl-2-naphthylmethylamine and the like.
The reduction reaction is usually conducted, for example, by a process which comprises reacting the imine compound of formula (7) with a reducing agent such as a metal hydride or the like, alternatively with hydrogen in the presence of a catalyst.
Examples of the metal hydride include lithium aluminum hydride, sodium borohydride and borane and the like. Borane includes diborane, borane-THF, a borane-sulfide complex, a borane-amine complex and the like.
The amount of the reducing agent to be used is usually within the range of approximately from 0.25 to 5 moles, preferably approximately from 0.25 to 2 moles per mol of the imine compound (7) in the case where lithium alminum hydride or sodium borohydride is used.
When borane is used, the amount of borane to be used, on a borone basis, is usually within the range of approximately from 0.3 to 5 moles, preferably approximately from 0.3 to 3 moles per mol of the imine compound (7).
The reduction reaction is usually conducted in an inert solvent. Examples of the inert solvents include ethers such as diethyl ether, t-butyl methyl ether, n-butyl ether, tetrahydrofuran or the like, aromatic hydrocarbons such as benzene, toluene, xylene or the like, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, chlorobenzene or the like.
When sodium borohydride is used as a reducing agent, a lower alcohol such as methanol, ethanol, isopropyl alcohol or the like as well as the aforementioned solvents. The solvent may be used alone or as a mixture thereof. The amount of the solvent to be used is not particularly limited.
The reaction is usually conducted within a temperature range of approximately of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9220xc2x0 C. to 100xc2x0 C.
After completion of the reaction, the optically active amine compound (4) is usually obtained, for example, by treating the resulting reaction mixture with water, acetic acid or an inorganic acid, and then extracted with a hydrophobic organic solvent under alkaline conditions, which was made by adding an appropriate amount of a base, phase separation of the organic phase and concentration thereof under a neutral or weakly basic condition. The product may be further purified by recrystallization, and/or column chromatography using silica gel, etc., if necessary.
Examples of the: catalyst to be used for hydrogenation include Raney nickel, palladium-carbon, platinum dioxide, platinum black and the like.
The amount of such a catalyst to be used is usually from 0.1 to 100% by weight, preferably from 0.5 to 50% by weight per 1 part by weight of the imine compound (7).
An inert solvent may be used in the hydrogenation reaction. Examples of the solvent include alcohols such as methanol, ethanol, isopropyl alcohol or the like, ethers such as diethyl ether, t-butyl methyl ether, n-butyl ether, tetrahydrofuran or the like, esters such as ethyl acetate, aromatic hydrocarbons such as benzene, toluene, xylene or the like, water, etc. These solvents may be used alone or as a mixture thereof. The amount of the solvent to be used is not particularly limited.
The hydrogenation is usually conducted within the range of approximately from xe2x88x9230xc2x0 C. to 150xc2x0 C., preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C.
The hydrogenation is usually conducted at a pressure of approximately from 0 to 10 MPa (0 to 100 kg/cm2), preferably approximately from 0 to 5 MPa (0 to 50 kg/cm2).
After completion of the reaction, the optically active amine compound (4) can be obtained, for example, by removing the catalyst by filtration, followed by concentrating the filtrate. The desired product may be further purified by recrystallization and/or column chromatography using silica gel, if necessary.
The imine compound (7) is usually obtained by a process, which comprises reacting the optically active amine (5) with the benzyloxybenzaldehyde (6).
In the optically active amine (5), R11 and R21 are as defined above for the optically active compound of formula (4).
Examples of the optically active amine (5) include optical isomers of xcex1-methylbenzylamine, 1-(1-naphthyl)ethylamine, xcex1,4-dimethylbenzylamine, 4-isopropyl-xcex1-methylbenzylamine, 4-nitro-xcex1-methylbenzylamine, 4-bromo-xcex1-methylbenzylamine, xcex1-ethylbenzylamine, xcex1-isopropylbenzylamine, 1-phenyl-2-(p-tolyl)ethylamine and the like. These amines are commercially available or can be readily obtained by a known method. Alternatively, the optically active amine (5) can be obtained by a similar manner as disclosed in a reference such as Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart and the like.
Examples of the benzyloxybenzaldehyde of formula (6): R31xe2x80x94CHO include 3-benzyloxybenzaldehyde and 4-benzyloxybenzaldehyde. These aldehydes are commercially available.
The optically active amine (5) is usually reacted with the benzyloxybenzaldehyde of formula (6) in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, isopropyl alcohol or the like, ethers such as diethyl ether, t-butyl methyl ether, n-butyl ether, tetrabydrofuran or the like, aromatic hydrocarbons such as benzene, toluene, xylene or the like, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, chlorobenzene or the like.
The solvent may be used alone or as a mixture thereof.
The amount of the benzyloxybenzaldehyde (6) is usually 1 to 1.2 moles per mole of the optically active amine (5).
The reaction temperature is usually within the range of from 0xc2x0 C. to 200xc2x0 C., preferably from 0xc2x0 C. to 150xc2x0 C.
Although the obtained imine compound (7) can be isolated by evaporation and the like, it may be used in the subsequent reaction as it is without being isolated.
Next descriptions will be made to the optically active amine compound of formula (8) as defined above, a process for producing the same, the imine compound (11) and processes of using and producing the same.
In the novel optically active compound of formula (8), the halogen atom represented by X1 to X5 have the same meanings as defined above.
The lower alkyl group represented by R22 or X2 to X5 include a C1-C4 alkyl group as specified for R2 above.
Preferably, X1 and X3 represent halogen atoms such as chlorine and X2, X4 and X6 represent hydrogen atoms.
The lower alkyl group and the lower alkoxy group on the aryl group in R32 include C1-C4 alkyl group and C1-C4 alkoxy group respectively.
Examples of the aryl group include C6-C10 aryl group such as a phenyl or naphthyl group.
Examples of the C6-C10 aryl group substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, an aryl group (e.g. a phenyl or naphthyl group) and an aryloxy group (e.g. a phenoxy or naphthoxy group), in R32 include
a 1-naphthyl group,
a 2-naphthyl group, a 4-methylphenyl group, a 4-ethylphenyl group,
a 4-propylphenyl group, a 4-isopropylphenyl group, a 4-t-butylphenyl group,
a 2,5-dimethylphenyl group, a 2,4,6-trimethylphenyl group,
a 2-methoxyphenyl group, a 4-methoxyphenyl group,
a 2-ethoxyphenyl group, a 2-propoxyphenyl group,
a 3,4-dimethoxyphenyl group, a 3-phenoxyphenyl group, and
a 4-phenylphenyl group. Among these groups, preferred are 3-phenoxyphenyl group and a 4-phenylphenyl group.
Specific examples the optically active amine compound of formula (8) or salts thereof include optically active isomers of
N-(4-methylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(2-methylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(4-methoxybenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(2-ethoxybenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxybenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2-chloro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-dimethylbenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2-methoxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-methoxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2-ethoxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-dimethoxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2-methoxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-methoxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2-ethoxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-methylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(4-isopropylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2-methoxylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(4-methoxylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2-ethoxylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(3-phenoxybenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(4-phenoxybenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2-phenylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(3-phenylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine,
N-(4-phenylbenzyl)-2,4-diethyl-xcex1-methylbenzylamine, and salts thereof with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or the like.
The optically active amine compound of formula (8) can be, for example, obtained by a process, which comprises subjecting the imine compound of formula (11) to a reduction reaction.
In the imine compound of formula (11), X1 to X5, R22 and R32 respectively have the same meanings as defined for the optically active amine compound of formula (8) above.
Specific examples of the imine compound (11) include:
N-(4-methylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2-chloro-xcex1-methylbenzylamine,
N-(2-methylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2,5-methylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(isopropylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,3-dichloro-xcex1-methylbenzylamine,
N-(4-methylbenzylidene)-2,4-dichloro-xcex1-methybenzylamine,
N-(2,5-methylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(4-methylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzylidene)-2,4-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,5-dichloro-xcex1-methylbenztlamine,
N-(4-methoxylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,5-dichloro-xcex1-methylbenzyIamine,
N-(3-phenoxybenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,5-dichloro-xcex1-methylbenzylamine,
N-(4-methylbenzylamine)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,6-dichloro -xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,6-dichloro-xcex1-methylbenzylamine,
N-(4-methybexzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,4,6-trichloro-xcex1-methylbenzylamine,
N-(4-methylbenzylamine)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2,5-dixnethylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,3,4trichloro-xcex1-methylbenzylamine,
N-(4-isopropylbexnzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-phetoxybenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,3,4-trichloro-xcex1-methylbenzylamine,
N-(4-methylbenzylamine)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4methoxylbenzylidenie)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-pheanoxybenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,4-difluoro-xcex1-methylbenzylamine,
N-(4-methylbenzyhidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2,5-dethylbenzylidne)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzyldene)-2,4-dibromo-xcex1-metylbenzylamine,
N-(3-phenoxybenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,4-dibromo-xcex1-methylbenzylamine,
N-(4methylbenzylamine)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2,4,6-tdimethylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2-methoxylbenzylideiie)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,4-diiodo-xcex1-metbylbenzylamine,
N-(4-phenylbenzylidene)-2,4-diiodo-xcex1-methylbenzylamine,
N-(4-methylbenzylamine)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2,5-dimetylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2,46-trimethylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene,)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)2,4-dimethyl-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-phenoxybenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,4-dimethyl-xcex1-methylbenzylamine,
N-(4-methylbenzylamine)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2,5-dimethylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2,4,6-trimethylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(4-isopropylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2-methoxylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(4-methoxylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2-ethoxylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(3,4-dimethoxylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(3-phenoxybenzylidene)-2,4 diethyl-xcex1-methylbenzylamiue,
N-(4-phenoxybenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(2-phenylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(3-phenylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine,
N-(4-phenylbenzylidene)-2,4-diethyl-xcex1-methylbenzylamine, and the like.
The reduction reaction of the imine compound (11) is usually conducted by a process which comprises reacting the imine compound (11) with a reducing agent such as a metal hydride or the like, alternatively with hydrogen in the presence of a catalyst.
Examples of the metal hydride include lithium aluminum hydride, sodium borohydride and borane and the like. Borane includes diborane, borane-THF, a borane-suliEde complex, a borane-amine complex and the like.
The amount of the reducing agent to be used is usually within the range of approximately from 0.25 to 5 moles, preferably approximately from 0.25 to 2 moles per mol of the imine compound (11) in the case where lithium alminum hydride or sodium borohydride is used.
When borane is used, the amount of borane to be used, on a borone basis, is usually within the range of approximately from 0.3 to 5 moles, preferably approximately from 0.3 to 3 moles per mol of the imine compound (11).
The reduction reaction is usually conducted in au inert solvent. Examples of the inert solvents include those as specified for the reduction reaction of the imine compound of formula (7) above.
When sodium borohydride is used as a reducing agent, a lower alcohol such as methanol, ethanol, isopropyl alcohol or the like can be used as well as the aforementioned solvents. The solvent may be used alone or as a mixture thereof. The amount of the solvent to be used is not particularly limited.
The reaction is usually conducted within a temperature range of approximately of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9220xc2x0 C. to 100xc2x0 C.
After completion of the reaction, the optically active amine compound (8) is usually obtained, for example, by treating the resulting reaction mixture with water, acetic acid or a mineral acid, and then being made alkaline, followed by extraction with a hydrophobic organic solvent, phase separation of the organic phase and concentration thereof under a neutral or weakly basic condition. The product may be further purified by recrystallization, andjor column chromatography using silica gel, etc., if necessary.
Examples of the catalyst to be used for the reduction with hydrogen include Raney nickel, palladium-carbon, platinum dioxide, platinum black and the like.
The amount of such a catalyst to be used is usually from 0.1 to 100% by weight, preferably from 0.5 to 50% by weight per 1 part by weight of the imine compound (11).
The hydrogenation reaction in the presence of a catalyst is usually conducted in an inert solvent. Examples of the solvent include those as specified for the reduction reaction of the imine compound of formula (7) above. The amount of the solvent to be used is not particularly limited.
The hydrogenation is usually conducted within the range of approximately from xe2x88x9230xc2x0 C. to 150xc2x0 C., preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C.
The hydrogenation is usually conducted at a pressure of approximately from 0 to 10 MPa (0 to 100 kg/cm2), preferably approximately from 0 to 5 MPa (0 to 50 kg/cm2).
After completion of the reaction, the optically active amine compound (8) can be obtained, for example, by removing the catalyst by filtration, followed by concentrating the filtrate. The desired product may be further purified by recrystallization and/or column chromatography using silica gel, if necessary.
Then imine compound of formula (11) can be obtained, for example, by a process which comprises reacting the aldehyde compound of formula (10) with an optically active amine compound of formula (9).
Examples of the aldehyde compound of formula (10) include
4-methylbenzaldehyde, 2,5-dimethylbenzaldehyde,
2,4,6-trimethylbenzaldehyde, 4-isopropylbenzaldehyde,
2-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-ethoxybenzaldehyde,
3,4dimethoxybenzaldehyde, 5-fluoro-2-methoxybenzaldehyde,
3-phenoxybenzaldehyde, 4-phenoxybenzaldehyde, 2-phenylbenzaldehyde,
3-phenylbenzaldehyde, 4-phenylbenzaldehyde, and the like. These aldehydes are commercially available or may be obtained by a similar manner as disclosed in references such as Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart and the like.
Examples of the optically active amine compound of formula (9) include 2,4-dichloro-xcex1-mepthylbenzylamine and the like.
The optically active amine (9) is usually reacted with the benzaldehyde of formula (10) in a solvent. Examples of the solvent include those specified above for the reaction of the optically active amine compound of formula (5) with the benzyloxybenzaldehyde (6).
The optically active amine (9) are commercially available or can be obtained by a similar manner as disclosed in references such as Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart and the like.
The amount of the benzaldehyde (10) is usually 1 to 1.2 moles per mole of the optically active amine (9).
The reaction is usually conducted within the range of from 0xc2x0 C. to 200xc2x0 C., preferably from 0xc2x0 C. to 150xc2x0 C.
Although the obtained imine compound (11) can be isolated, for example, by evaporation and the like, it may be used, as it is, in the subsequent reaction without being isolated.